Assessing liver fibrosis without biopsy in patients with HCV or NAFLD

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Release date: March 1, 2019
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Staging of liver fibrosis is increasingly done using noninvasive methods, in some cases obviating the need for liver biopsy. Scores based on laboratory values and demographic variables have been developed and validated for assessing fibrosis in patients with hepatitis C virus (HCV) infection and nonalcoholic fatty liver disease (NAFLD), as have several imaging methods that measure shear-wave velocity, a reflection of fibrosis severity.


  • Liver biopsy remains the gold standard for determining fibrosis stage but is expensive and entails risk of complications.
  • For patients infected with HCV, fibrosis stage should be determined with transient elastography, a transthoracic ultrasonographic technique that measures shear-wave velocity.
  • For patients with cirrhosis, transient elastography combined with a platelet count can detect developing portal hypertension and determine whether to screen for esophageal varices.
  • For NAFLD, combined elastography and NAFLD fibrosis score—which incorporates patient characteristics and laboratory test results—should be used to determine the need for liver biopsy.



Staging of liver fibrosis, important for determining prognosis in patients with chronic liver disease and for the need to start screening for complications of cirrhosis, was traditionally done only by liver biopsy. While biopsy is still the gold standard method to stage fibrosis, noninvasive methods have been developed that can also assess disease severity.

This article briefly reviews the epidemiology and physiology of chronic liver disease and the traditional role of liver biopsy. Pros and cons of alternative fibrosis assessment methods are discussed, with a focus on their utility for patients with nonalcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV) infection.


Chronic liver disease is associated with enormous health and financial costs in the United States. Its prevalence is about 15%,1 and it is the 12th leading cause of death.2 Hospital costs are estimated at about $4 billion annually.3

The most common causes of chronic liver disease are NAFLD (which may be present in up to one-third of the US population and is increasing with the epidemic of obesity), its aggressive variant, nonalcoholic steatohepatitis (NASH) (present in about 3% of the population), and HCV infection (1%).4,5

Since direct-acting antiviral agents were introduced, HCV infection dropped from being the leading cause of liver transplant to third place.6 But at the same time, the number of patients on the transplant waiting list who have NASH has risen faster than for any other cause of chronic liver disease.7


Fibrosis staging systems for HCV and NAFLD
With any form of liver disease, collagen is deposited in hepatic lobules over time, a process called fibrosis. Both HCV infection and NASH involve necroinflammation in the liver, hepatocyte apoptosis, and activation of stellate cells, leading to progressive collagen deposition in hepatic lobules. Fibrosis typically starts in the region of the central vein and portal tracts and eventually extends to other areas of the lobule.
Findings on liver biopsy in nonalcoholic fatty liver disease and hepatitis C virus infection.

Figure 1. Findings on liver biopsy in nonalcoholic fatty liver disease and hepatitis C virus infection.

Determining fibrosis severity is critical when a patient is diagnosed with chronic liver disease, as it predicts long-term clinical outcomes and death in HCV8 and NAFLD.9 Different staging systems have been developed to reflect the degree of fibrosis, based on its distribution as seen on liver biopsy (Table 1, Figure 1).

In HCV infection, advanced fibrosis is defined as either stage 4 to 6 using the Ishak system10 or stage 3 to 4 using the Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) system.11

In NAFLD, advanced fibrosis is defined as stage 3 to 4 using the NASH Clinical Research Network system.12

Staging fibrosis is also important so that patients with cirrhosis can be identified early to begin screening for hepatocellular carcinoma and esophageal varices to reduce the risks of illness and death. In addition, insurance companies often require documentation of fibrosis stage before treating HCV with the new direct-acting antiviral agents.


Although invasive, liver biopsy remains the gold standard for determining fibrosis stage. Liver biopsies were performed “blindly” (without imaging) until the 1990s, but imaging-guided biopsy using ultrasonography was then developed, which entailed less pain and lower complication and hospitalization rates. Slightly more hepatic tissue is obtained with guided liver biopsy, but the difference was deemed clinically insignificant.13 Concern initially arose about the added cost involved with imaging, but imaging-guided biopsy was actually found to be more cost-effective.14

In the 2000s, transjugular liver biopsy via the right internal jugular vein became available. This method was originally used primarily in patients with ascites or significant coagulopathy. At first, there were concerns about the adequacy of specimens obtained to make an accurate diagnosis or establish fibrosis stage, but this limitation was overcome with improved techniques.15,16 Transjugular liver biopsy has the additional advantage of enabling one to measure the hepatic venous pressure gradient, which also has prognostic significance; a gradient greater than 10 mm Hg is associated with worse prognosis.17

Disadvantages of biopsy: Complications, sampling errors

Liver biopsy has disadvantages. Reported rates of complications necessitating hospitalization using the blind method were as high as 6% in the 1970s,18 dropping to 3.2% in a 1993 study.19 Bleeding remains the most worrisome complication. With the transjugular method, major and minor complication rates are less than 1% and 7%, respectively.15,16 Complication rates with imaging-guided biopsy are also low.

Liver biopsy is also prone to sampling error. The number of portal tracts obtained in the biopsy correlates with the accuracy of fibrosis staging, and smaller samples may lead to underestimating fibrosis stage. In patients with HCV, samples more than 15 mm long led to accurate staging diagnosis in 65% of patients, and those longer than 25 mm conferred 75% accuracy.20 Also, different stages can be diagnosed from samples obtained from separate locations in the liver, although rarely is the difference more than a single stage.21

Histologic evaluation of liver biopsies is operator-dependent. Although significant interobserver variation has been reported for degree of inflammation, there tends to be good concordance for fibrosis staging.22,23

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